1. Field of the Invention
The invention relates generally to research directed to, and medical treatment of, Inflammatory Bowel Disease ("IBD"). More specifically, the invention relates to the discovery of a correlation between IBD and an intestinal parasitic microsporidia infection. The invention therefore involves, in preferred aspects, methods for diagnosing IBD or other microsporidia infection, and methods for treating a patient, preferably a human patient, having IBD or other microsporidia infection. More particularly, the invention relates in preferred aspects to the use of pharmaceutically-active compounds for treating a patient suffering from IBD.
2. Discussion of Related Art
Inflammatory bowel disease (IBD) is a group of chronic disorders that cause inflammation and/or ulceration in the small and large intestines. Most often, IBD is classified as ulcerative colitis or Crohn's disease, but may be referred to as diverticulitis, colitis, enteritis, ileitis, and proctitis. Ulcerative colitis has also been commonly referred to as "unspecific ulcerative colitis" or "idiopathic ulcerative colitis" because physicians and scientists have been unsuccessful in their attempts to identify the etiological agent causing the disease. Ulcerative colitis causes ulceration and/or inflammation of the inner lining of the colon and rectum, while Crohn's disease is an inflammation that extends into the deeper layers of the intestinal wall. Crohn's disease may involve any segment of the digestive tract, including the mouth, esophagus, stomach, and small intestine, although characteristically the region of greatest involvement is the distal one-quarter of the small intestine and the proximal colon. Ulcerative colitis is typically isolated in the proximity of the colon. Ulcerative colitis and Crohn's disease cause similar symptoms that often resemble other conditions, such as irritable bowel syndrome (spastic colitis); therefore, the correct diagnosis may take some time, and is certainly not straightforward.
In ulcerative colitis, the inner lining of the large intestine (colon or bowel) and rectum become inflamed. The inflammation usually begins in the rectum and lower (sigmoid) intestine and spreads upward to the entire colon. Ulcerative colitis rarely affects the small intestine; however, the lower section, the ileum, is sometimes involved. The inflammation causes the colon to empty frequently, resulting in diarrhea. As cells on the surface of the lining of the colon die and slough off, ulcers (tiny open sores) form, causing pus, mucus and bleeding. Because ulcerative colitis is associated with mucosal injury, it is desirable to detect ulcerative colitis early in the patient's life, and to be able to distinguish ulcerative colitis from functional disorders such as irritable bowel syndrome. Early intervention can improve the long-range prognosis for the patient.
Ulcerative Colitis is a cosmopolitan disease estimated to affect 6 to 10 people per 10,000. There is little percentage difference among Caucasians, Blacks, and Asians, but the incidence in women is slightly higher than that in man. It occurs most often in young people ages 15 to 40, although children and older people sometimes develop the disease, these cases being rare. The above-estimated incidence rate is believed to be an underestimation of the actual number of people suffering from the disease. One reason for this belief is the difficulty in diagnosing the disease. Another reason for the possible underestimation of the number of people infected by the disease is the fact that it is not considered a reportable disease. Most patients are treated as outpatients and many statistical figures include only those patients who are periodically admitted into the hospital, reducing the real incidence statistics. Even those cases treated as outpatient, however, are very important in characterizing the morbidity and mortality of the disease. There is no doubt that treatment of IBD has become one of the most important problems of modem medicine.
Ulcerative colitis is not a new disease. Clinical descriptions that are very suggestive of ulcerative colitis can be found dating back to the Roman Empire. Until Giovanni Morgani introduced the discovery of the relationship between the symptoms of the disease and its morbid anatomical aspects, in 1761, the diagnostic conclusions lacked scientific backing. In the Nineteenth Century, the golden century for medicine, difficulties existed in the efforts to distinguish ulcerative colitis from infectious or parasitic dysentery. Even so, in 1865, during the American Civil War, there were descriptions of probable cases of ulcerative colitis. The superficial inflammation of the mucosa, especially the crypts/follicles was pointed out and, according to medical officials of the time, this feature contributed to the differentiation between ulcerative colitis and infectious dysentery. More credit has been given, however, to Wilks & Moxon, who in 1875, published the first edition of the book "Lectures and Pathological Anatomy." Even though they did not mention unspecific ulcerative colitis in the first edition, they described and defined what they called "simple ulcerative colitis" in the chapter "The Inflammations of the Large Intestine." The data that was reported referred to post-mortem macroscopical findings.
One of the most significant contributions to the knowledge about unspecific ulcerative colitis was the work of Hale-White, contemporary to Wilks, published in 1888. This author described 29 cases of inflammatory intestinal lesions. A more in-depth analysis of his findings leads us to possible cases of ulcerative colitis (including neoplasm and toxic megacolon), Crohn's disease (involving small intestine and colon), tuberculosis, typhoid fever, lymphoma, ischemia, appendicitis, and uraemic colitis. Hale-White, in 1895, published a new article entitled "Colitis," clarifying to the medical community the concept of non-infectious ulcerative colitis. Finally, with the advent of a procedure termed rectosigmoidoscopy, and also contrasted radiological colon tests, starting in the Twentieth Century, the study of unspecific ulcerative colitis was directed to those patients still living. Until then the descriptions and conclusions were based only on post-mortem data.
Ulcerative colitis evolves in varied patterns. Typically, the disease is progressive, characterized by episodes of exacerbation and remission. Generally, the clinical course is more severe when the disease first appears early in the patient's life. The prognosis is poorer when the extent of the involvement is greater, and is generally more favorable when only the sigmoid colon and the rectum are involved. There are instances of fulminating initial symptoms and others in which the symptoms are initially weak but later become severe. There may be huge variations in the intermediary phases as to the diarrhea, sometimes accompanied by mucous, mucous and blood, or mucous-blood and pus (which is characterized as bio-mucous-sanguinolent). There are cases in which the daily episodes of diarrhea may reach 30, but those are exceptions. Generally, when the severity of the disease is considered to be medium to high, the number of daily episodes is between four and 10.
While the most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea, patients also may suffer fatigue, weight loss, loss of appetite, rectal bleeding, and loss of body fluids and nutrients. Severe bleeding can also lead to anemia, and patients sometimes also develop skin lesions, joint pain, inflammation of the eyes, or liver disorders. To date, no reason has been substantiated for the link between colitis and these problems outside the bowel. Scientists think these complications may occur when the immune system triggers inflammation in other parts of the body. These disorders are usually mild and go away when the symptoms of colitis are treated.
Because the etiological agent causing IBD has for so long remained undetermined, diagnosis of, for example, ulcerative colitis and Crohn's disease has been very problematic and its cure has remained elusive, except through surgical removal of the colon. Medical treatment has historically been directed toward simply treating the symptoms of the disease, thereby decreasing the number, frequency and severity of acute exacerbations of IBD and preventing secondary complications. At best, however, the results have been disappointing. With respect to the difficulty of diagnosing the disease, only in recent years has the diagnosis been done by the most correct and widely acceptable method, rectosigmoidoscopy. This procedure, which typically utilizes a videocolonscope, is a useful way to diagnose the intestinal alterations associated with ulcerative rectum colitis, colitis, diverticulitis and Crohn's disease, because it provides visualization of the intestinal mucous. Videocolonoscopy is commonly followed by a biopsy, allowing the physician to further observe a site of inflammation. The typical characteristics of the lesions may then be identified by their morphophysiological characteristics, thereby allowing the physician to reach a conclusion as to the specific condition. Given that this is a technique not readily accessible to lower income patients, however, there are speculations that there are many misdiagnosed cases that are taken as simple viral infections, or even bacterial diarrhea, masking the real numbers of cases.
Although much scientific evidence shows that people with ulcerative colitis have abnormalities of the immune system, doctors have not been able to determine conclusively whether these abnormalities are a cause or result of the disease. A number of studies have suggested that components of the immune system may mediate or contribute to injury observed in the colonic mucosa, but it remains unclear what initiates the pathogenic processes. It has been suggested that a primary abnormality of the immune system and its regulation might serve as primary initiating factors, or that the disease process might be initiated by an infectious agent and the injury then perpetuated through immune-mediated or other processes. One leading theory has suggested that some agent, possibly a virus or an atypical bacterium, interacts with the body's immune system to trigger an inflammatory reaction in the intestinal wall. Although the mucosal injury observed during episodes of acute disease can resemble the effects of any of a number of recognized infectious agents, no transmissible infectious agent was consistently identified with ulcerative colitis. Alternatively, it has been suggested that aberrant structures in the colonic mucosa might increase susceptibility of the colonic mucosa to a lumen factor, predisposing the colonic mucosa to injury by causing a defect in the mucosal barrier or initiating inappropriate activation of injurious immune-mediated processes.
About half of patients have only mild symptoms. Others suffer frequent fever, bloody diarrhea, nausea, and severe abdominal cramps. Only in rare cases, when complications occur, is the disease fatal. There may be remissions, periods when the symptoms go away, that last for months or even years. However, most patients' symptoms eventually return. This changing pattern of the disease can make it hard for the doctor to tell when treatment has helped.
Ulcerative colitis has historically been thought to be untreatable and incurable and a patient with the disease must learn to live with it and use, for indefinite periods, medication that is meant to control it, such as, for example, sulfanilamide, 5ASA, and corticoids, which provide only palliative activity. Patients with either mild or severe colitis are usually treated with sulfasalazine, which can be used for as long as needed; however, side effects such as nausea, vomiting, weight loss, heartburn, diarrhea, and headache occur in some cases. Patients who do not do well on sulfasalazine often react well to related drugs known as 5-ASA agents. In some cases, patients with severe disease, or those who cannot take sulfasalazine-type drugs are given adrenal steroids (drugs that help control inflammation and affect the immune system) such as prednisone or hydrocortisone. All of these drugs can be used in oral, enema, or suppository forms. Additionally, other drugs may be given to relax the patient or to relieve pain, diarrhea, or infection; however, corticosteroids and sulfasalazine are the only drugs that have been shown to shorten an acute attack of ulcerative colitis. (Truelove, S. C., Witts, L. J., Cortisone in ulcerative colitis and the indications for colectomy. World J. Surg. 1988; 12:142-7). Corticosteroids achieve a rapid remission more frequently than sulfasalazine; however, the combination of these agents is widely used for treatment of colitis attacks (Truelove, S. C., Witts, L. J., Cortisone in ulcerative colitis and the indications for colectomy. World J. Surg. 1988; 12:142-7).
Patients with ulcerative colitis occasionally have symptoms severe enough to require hospitalization. In these cases, the doctor will try to correct malnutrition and to stop diarrhea and loss of blood, fluids, and mineral salts. To accomplish this, the patient may need a special diet, feeding through a vein, medications, or sometimes, surgery.
The risk of colon cancer is greater than normal in patients with widespread ulcerative colitis. The risk may be as high as 32 times the normal rate in patients whose entire colon is involved, especially if the colitis exists for many years. The most severe and alarming form of ulcerative colitis is the kind in which the symptoms persist for 15 years or longer. The percentage of these cases that evolve into colon cancer surpasses 17%.
About 20 to 25% of ulcerative colitis patients eventually require surgery for removal of the colon because of massive bleeding, chronic debilitating illness, perforation of the colon, or risk of cancer. Sometimes the doctor will recommend removing the colon when other medical treatment fails or when the side effects of steroids or other drugs threaten the patient's health. The most common surgery is the proctocolectomy, the removal of the entire colon and rectum, with ileostomy, creation of a small opening in the abdominal wall where the tip of the lower small intestine, the ileum, is brought to the skin's surface to allow drainage of waste. The opening (stoma) is about the size of a quarter and is usually located in the right lower corner of the abdomen in the area of the beltline. A pouch is worn over the opening to collect waste and the patient empties the pouch periodically.
Proctocolectomy with continent ileostomy is an alternative to the standard ileostomy. In this operation, the surgeon creates a pouch out of the ileum inside the wall of the lower abdomen. The patient is able to empty the pouch by inserting a tube through a small leak-proof opening in his or her side. Creation of this natural valve eliminates the need for an external appliance. However, the patient must wear an external pouch for the first few months after the operation.
Sometimes an operation that avoids the use of a pouch can be performed. In an ileoanal anastomosis ("pull-through operation"), the diseased portion of the colon is removed and the outer muscles of the rectum are preserved. The surgeon attaches the ileum inside the rectum, forming a pouch, or reservoir, that holds the waste. This allows the patient to pass waste through the anus in a normal manner, although the bowel movements may be more frequent and watery than usual.
In view of the above background, there is a great need in the field of medicine for a method of treating patients suffering from IBD, wherein the treatment avoids the need for highly invasive and life-altering surgical procedures, is directed to the disease itself, and does not merely treat the symptoms. Further, there is a great need in the art for a method whereby a patient may be screened in the first instance for the disease, thereby reducing the risk of misdiagnosis and resulting ineffective treatments. The present invention satisfies these and other needs in the field of treating IBD.